The long range objective of this research is to use neurophysiological and psychophysical techniques to develop a better understanding of pain perception. This strategy of correlative neurophysiological and psychophysical studies is a powerful technique to develop an understanding of neural encoding mechanisms. In our research we correlate the response of primary nociceptive afferents, obtained from single fiber recordings in the anesthetized monkey, with the response of human subjects, based on ratings of subjective magnitude. With this approach we have been able to make major inroads regarding the understanding of the peripheral as well as central neural mechanisms of pain and hyperalgesia. These studies provide a foundation to purse research on patients in order to understand and treat neuropathic pain. This proposal builds on prior work by continuing investigations into the role of nociceptors in normal pain sensation and by continuing neurophysiological and psychophysical studies of the mechanisms of hyperalgesia at the site of injury (primary hyperalgesia) and of hyperalgesia in the uninjured skin surrounding an injury (secondary hyperalgesia). These studies of primary and secondary hyperalgesia form the basis for investigations of hyperalgesia in neuropathic pain, a common and debilitating form of chronic pain. Numerous questions will be probed to address such issues as: (1) how does the branching structure of nociceptors affect signal processing? (2) What is the basis of fatigue in nociceptors? (3) Capsaicin is a potent drug in causing pain and hyperalgesia but also has therapeutic potential. Which classes of nociceptors signal the pain from capsaicin, and which classes are vulnerable to the toxic effects of capsaicin? (4) Two models of secondary hyperalgesia will be tested to gather information about the likely central nervous system mechanisms of this pathological feature of pain. (5) Finally these studies of hyperalgesia in normal volunteers will be directly applied to test highly focused hypotheses regarding the mechanisms and possible treatments of neuropathic pain in patients. This hypothesis driven research interrelates basic and clinical research in a mater that has excellent potential for promoting the understanding and treatment of pain.